Acromegaly accompanied by diabetes mellitus and polycystic kidney disease.

Acromegaly is characterized by autonomous excessive growth hormone (GH) secretion, generally due to GH-producing pituitary adenoma, and is associated with various systemic comorbidities including diabetes mellitus. Polycystic kidney disease (PKD) is characterized by the growth of numerous cysts in the kidneys that deteriorate renal function. While possible renal effects of excessive GH exposure have been a current issue in experimental medicine, only five cases of coexisting acromegaly and PKD have been reported previously, and little is known regarding the influence of acromegaly on renal disease. We treated a 50-year-old male with diabetes mellitus who showed a sudden and rapid decline of renal function along with increasing proteinuria, which led to diagnoses of PKD and acromegaly. His urinary protein levels were increased together with excessive GH secretion and worsening glycemic control. An increase of total kidney volume was also noted. Transsphenoidal surgery for the pituitary adenoma was successfully performed. Marked improvement of hyperglycemia and proteinuria were observed after the surgery, but renal function was unchanged. The patient's clinical course suggested common aspects of excessive GH secretion as an accelerating factor of the progression of diabetic nephropathy and PKD via direct and indirect pathways. Although coexisting acromegaly and PKD is clinically rare, vigilance for early diagnosis of acromegaly is appropriate in patients with diabetes and/or PKD, especially in those showing unexpected exacerbation of renal dysfunction.

Sphingosine kinase 1-interacting protein is a dual regulator of insulin and incretin secretion.

Our previous study demonstrated that sphingosine kinase 1-interacting protein (SKIP, or Sphkap) is expressed in pancreatic ß-cells, and depletion of SKIP enhances glucose-stimulated insulin secretion. We find here that SKIP is also expressed in intestinal K- and L-cells and that secretion of gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) as well as insulin are significantly increased, and blood glucose levels are decreased in SKIP-deficient (SKIP-/-) mice compared with those in wild-type mice. Plasma triglyceride (Tg), LDL cholesterol, and mRNA levels of proinflammatory cytokines in adipose tissues, livers, and intestines were found to be significantly decreased in SKIP-/- mice. The phenotypic characteristics of SKIP-/- mice, including adiposity and attenuation of basal inflammation, were abolished by genetic depletion of GIP. The improvement of glucose tolerance and lipid profiles in SKIP-/- mice were cancelled by GLP-1 receptor antagonist exendin-(9-39) treatment. In summary, depletion of SKIP ameliorates glucose tolerance by enhancing secretion of insulin and incretins, improves lipid metabolism, and reduces basal inflammation levels. Thus, inhibition of SKIP action may emerge as a new option for treatment of type 2 diabetes mellitus with metabolic dysfunction.-Liu, Y., Harashima, S., Wang, Y., Suzuki, K., Tokumoto, S., Usui, R., Tatsuoka, H., Tanaka, D., Yabe, D., Harada, N., Hayashi, Y., Inagaki, N. Sphingosine kinase 1-interacting protein is a dual regulator of insulin and incretin secretion.

To treat or not to treat: Assessing the role of anti-enterococcal therapy for intra-abdominal infections in patients with cancer.

The clinical significance of enterococci in intra-abdominal infections, particularly those caused by multiple organisms, remains unclear. There are no definitive guidelines regarding the use of empiric therapy with antimicrobial agents targeting enterococci. In this study, we evaluated the impact of the initial antimicrobial therapy administration of anti-enterococcal agents on the treatment of intra-abdominal infections in patients with cancer in whom enterococci were isolated from ascitic fluid cultures. This retrospective study was conducted at Shizuoka Cancer Center between January 1, 2014, and December 31, 2020, on all adult patients with cancer with enterococci in their ascitic fluid cultures. The primary outcome was all-cause mortality, and the secondary outcomes were composite outcomes consisting of three components (mortality, recurrence, and treatment failure) and the risk factors associated with all-cause mortality and composite outcomes. In total, 103 patients were included: 61 received treatment covering enterococci, and 42 did not. The mortality rates did not differ significantly between the treated and untreated groups (treated: 8/61 [13.1%]; untreated: 5/42 [11.9%]; p = 1.00). Additionally, no significant difference was observed between the groups in terms of composite outcomes (treated group: 11/61 [18.0%]; untreated group: 9/42 [21.4%]; p = 0.80). Multivariate analysis showed that performance status (PS2-4; p < 0.0001) was an independent risk factor for mortality. The composite outcome was also significantly higher for PS2-4 (p = 0.007). Anti-enterococcal treatment was not associated with mortality or the composite outcome. In patients with cancer and intra-abdominal infections caused by enterococci, anti-enterococcal therapy was not associated with prognosis, whereas PS2 or higher was associated with prognosis. The results of this study suggest that the initial routine administration of anti-enterococcal agents for intra-abdominal infections may not be essential for all patients with cancer. To substantiate these findings, validation by a prospective randomized trial is warranted.

An analysis of intestinal morphology and incretin-producing cells using tissue optical clearing and 3-D imaging.

Tissue optical clearing permits detailed evaluation of organ three-dimensional (3-D) structure as well as that of individual cells by tissue staining and autofluorescence. In this study, we evaluated intestinal morphology, intestinal epithelial cells (IECs), and enteroendocrine cells, such as incretin-producing cells, in reporter mice by intestinal 3-D imaging. 3-D intestinal imaging of reporter mice using optical tissue clearing enabled us to evaluate both detailed intestinal morphologies and cell numbers, villus length and crypt depth in the same samples. In disease mouse model of lipopolysaccharide (LPS)-injected mice, the results of 3-D imaging using tissue optical clearing in this study was consistent with those of 2-D imaging in previous reports and could added the new data of intestinal morphology. In analysis of incretin-producing cells of reporter mice, we could elucidate the number, the percentage, and the localization of incretin-producing cells in intestine and the difference of those between L cells and K cells. Thus, we established a novel method of intestinal analysis using tissue optical clearing and 3-D imaging. 3-D evaluation of intestine enabled us to clarify not only detailed intestinal morphology but also the precise number and localization of IECs and incretin-producing cells in the same samples.

A novel splice-site mutation of the HNF1B gene in a family with maturity onset diabetes of the young type 5 (MODY5).

SUMMARY: Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes mellitus characterised by early onset and dominant inheritance. Delayed diagnosis or misdiagnosis as type 1 or type 2 diabetes mellitus is common. Definitive genetic diagnosis is essential for appropriate treatment of patients with MODY. The hepatocyte nuclear factor 1-beta (HNF1B) gene is responsible for MODY type 5 (MODY5), which has distinctive clinical features including renal disease. MODY5 should always be considered by clinicians in patients with early onset diabetes and renal anomalies. We report a case of a 30-year-old Japanese male with early-onset diabetes mellitus, renal anomalies and family history of diabetes that was suggestive of MODY5. Renal histology showed no evidence of diabetic nephropathy. Genetic testing revealed a novel heterozygous splice-site mutation of the HNF1B gene in the family members. It was strongly suggested that the mutation could underlie our patient's MODY5. LEARNING POINTS: Genetic diagnosis of MODY is relevant for appropriate treatment. Dominantly inherited early-onset diabetes mellitus with renal cysts suggests MODY5. Scanning the non-coding regions is important for not missing a mutation in HNF1B.

Generation and Characterization of a Novel Mouse Model That Allows Spatiotemporal Quantification of Pancreatic ß-Cell Proliferation.

Pancreatic ß-cell proliferation has been gaining much attention as a therapeutic target for the prevention and treatment of diabetes. In order to evaluate potential ß-cell mitogens, accurate and reliable methods for the detection and quantification of the ß-cell proliferation rate are indispensable. In this study, we developed a novel tool that specifically labels replicating ß-cells as mVenus+ cells by using RIP-Cre; R26Fucci2aR mice expressing the fluorescent ubiquitination-based cell cycle indicator Fucci2a in ß-cells. In response to ß-cell proliferation stimuli, such as insulin receptor antagonist S961 and diet-induced obesity (DIO), the number of 5-ethynyl-2'-deoxyuridine-positive insulin+ cells per insulin+ cells and the number of mVenus+ cells per mCherry+ mVenus- cells + mCherry- mVenus+ cells were similarly increased in these mice. Three-dimensional imaging of optically cleared pancreas tissue from these mice enabled quantification of replicating ß-cells in the islets and morphometric analysis of the islets after known mitogenic interventions such as S961, DIO, pregnancy, and partial pancreatectomy. Thus, this novel mouse line is a powerful tool for spatiotemporal analysis and quantification of ß-cell proliferation in response to mitogenic stimulation.

Single-Cell Transcriptome Analysis Dissects the Replicating Process of Pancreatic Beta Cells in Partial Pancreatectomy Model.

Heterogeneity of gene expression and rarity of replication hamper molecular analysis of ß-cell mass restoration in adult pancreas. Here, we show transcriptional dynamics in ß-cell replication process by single-cell RNA sequencing of murine pancreas with or without partial pancreatectomy. We observed heterogeneity of Ins1-expressing ß-cells and identified the one cluster as replicating ß-cells with high expression of cell proliferation markers Pcna and Mki67. We also recapitulated cell cycle transition accompanied with switching expression of cyclins and E2F transcription factors. Both transient activation of endoplasmic reticulum stress responders like Atf6 and Hspa5 and elevated expression of tumor suppressors like Trp53, Rb1, and Brca1 and DNA damage responders like Atm, Atr, Rad51, Chek1, and Chek2 during the transition to replication associated fine balance of cell cycle progression and protection from DNA damage. Taken together, these results provide a high-resolution map depicting a sophisticated genetic circuit for replication of the ß-cells.

Rb and p53 Execute Distinct Roles in the Development of Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PanNET) were classified into grades (G) 1 to 3 by the World Health Organization in 2017, but the precise mechanisms of PanNET initiation and progression have remained unclear. In this study, we used a genetically engineered mouse model to investigate the mechanisms of PanNET formation. Although pancreas-specific deletion of the Rb gene (Pdx1-Cre;Rbf/f ) in mice did not affect pancreatic exocrine cells, the α-cell/ß-cell ratio of islet cells was decreased at 8 months of age. During long-term observation (18-20 months), mice formed well-differentiated PanNET with a Ki67-labeling index of 2.7%. In contrast, pancreas-specific induction of a p53 mutation (Pdx1-Cre;Trp53R172H ) had no effect on pancreatic exocrine and endocrine tissues, but simultaneous induction of a p53 mutation with Rb gene deletion (Pdx1-Cre;Trp53R172H;Rb f/f ) resulted in the formation of aggressive PanNET with a Ki67-labeling index of 24.7% over the short-term (4 months). In Pdx1-Cre;Trp53R172H;Rbf/f mice, mRNA expression of Pten and Tsc2, negative regulators of the mTOR pathway, significantly decreased in the islet cells, and activation of the mTOR pathway was confirmed in subsequently formed PanNET. Thus, by manipulating Rb and p53 genes, we established a multistep progression model from dysplastic islet to indolent PanNET and aggressive metastatic PanNET in mice. These observations suggest that Rb and p53 have distinct roles in the development of PanNET. SIGNIFICANCE: Pancreas-specific manipulation of Rb and p53 genes induced malignant transformation of islet cells, reproducing stepwise progression from microadenomas to indolent (grade 1) and subsequent aggressive PanNETs (grade 2-3).

GPR40 activation initiates store-operated Ca2+ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic ß-cells.

The long-chain fatty acid receptor GPR40 plays an important role in potentiation of glucose-induced insulin secretion (GIIS) from pancreatic ß-cells. Previous studies demonstrated that GPR40 activation enhances Ca2+ release from the endoplasmic reticulum (ER) by activating inositol 1,4,5-triphosphate (IP3) receptors. However, it remains unknown how ER Ca2+ release via the IP3 receptor is linked to GIIS potentiation. Recently, stromal interaction molecule (STIM) 1 was identified as a key regulator of store-operated Ca2+ entry (SOCE), but little is known about its contribution in GPR40 signaling. We show that GPR40-mediated potentiation of GIIS is abolished by knockdown of IP3 receptor 1 (IP3R1), STIM1 or Ca2+-channel Orai1 in insulin-secreting MIN6 cells. STIM1 and Orai1 knockdown significantly impaired SOCE and the increase of intracellular Ca2+ by the GPR40 agonist, fasiglifam. Furthermore, ß-cell-specific STIM1 knockout mice showed impaired fasiglifam-mediated GIIS potentiation not only in isolated islets but also in vivo. These results indicate that the IP3R1/STIM1/Orai1 pathway plays an important role in GPR40-mediated SOCE initiation and GIIS potentiation in pancreatic ß-cells.

Retrospective analysis of liraglutide and basal insulin combination therapy in Japanese type 2 diabetes patients: The association between remaining ß-cell function and the achievement of the glycated hemoglobin target 1 year after initiation.

AIMS/INTRODUCTION: The glucose-lowering effects of the glucagon-like peptide-1 receptor agonist, liraglutide, have been shown to rely on remaining ß-cell function. However, the possible associations of remaining ß-cell function with the glucose-lowering effects of liraglutide in combination with basal insulin remain unknown and warrant investigation. MATERIALS AND METHODS: This was a single-center, retrospective, observational study carried out in a private hospital in Osaka, Japan. Type 2 diabetes patients who received a prescription change from insulin therapy, both multiple-dose insulin and basal insulin-supported oral therapy, to liraglutide and basal insulin combination and continued the therapy for 54 weeks without additional oral antidiabetic drugs or bolus insulin were retrospectively analyzed. RESULTS: Among the 72 participants who received a prescription change from multiple-dose insulin and basal insulin-supported oral therapy to liraglutide and basal insulin combination, 57 continued the therapy for 54 weeks. Of those who continued the therapy without receiving additional oral antidiabetic drugs or bolus insulin, seven participants achieved glycated hemoglobin < 7.0% at 54 weeks, but 30 participants did not. The participants who achieved glycated hemoglobin < 7.0% at 54 weeks had a significantly higher C-peptide immunoreactivity index, a ß-cell function-related index frequently used in Japanese clinical settings. The receiver operating curve analysis showed that the C-peptide immunoreactivity index cut-off value for the achievement of glycated hemoglobin <7.0% at 54 weeks is 1.103. CONCLUSIONS: The current findings show that the glucose-lowering effects of liraglutide rely on remaining ß-cell function, even when used with basal insulin; and suggest that liraglutide and basal insulin combination might require additional bolus insulin to fully compensate insulin insufficiency in individuals with reduced ß-cell function.

Relationship between deterioration of glycated hemoglobin-lowering effects in dipeptidyl peptidase-4 inhibitor monotherapy and dietary habits: Retrospective analysis of Japanese individuals with type 2 diabetes.

The present study was designed to assess possible relationships between deterioration of the glycated hemoglobin (HbA1c)-lowering effects in dipeptidyl peptidase-4 inhibitor (DPP4i) monotherapy and macronutrient intake among individuals with type 2 diabetes. Type 2 diabetes patients who began and continued DPP4i monotherapy without any prescription change for 1 year were retrospectively stratified into two groups: (i) patients who maintained their HbA1c levels during the 0.5- to 1-year period after DPP4i initiation (group A, ΔHbA1c [1-0.5 year] <0.4%, n = 53); and (ii) those whose HbA1c levels increased [group B, ΔHbA1c (1-0.5 year] ≥0.4%, n = 10). Group B had significantly higher ΔHbA1c (1-0.5 year), Δbodyweight (1-0.5 year) and fat intake, especially of saturated and monounsaturated fats; the carbohydrate and protein intake were similar between groups. Multiple regression analyses showed that fat intake, especially saturated fat intake, was significantly correlated with ΔHbA1c (1-0.5 year). Thus, dietary habits, especially saturated fat intake, might well contribute to deterioration of the HbA1c-lowering effects in DPP4i monotherapy.

Reply to the comment of Wilbrink et al. on Retrospective analysis of liraglutide and basal insulin combination therapy in Japanese type 2 diabetes: The association between remaining ß-cell function and the achievement of the HbA1c target 1 year after initiation.

We have reported that the HbA1c-lowering effects of liraglutide/basal insulin combination rely on remaining ß-cell function and that the cut-off value of the C-peptide immunoreactivity index (CPI), a ß-cell function-related index frequently used in Japanese clinical settings, is 1.103 for the achievement of HbA1c <7.0% at 54 weeks after initiating the liraglutide/basal insulin combination. Wilbrink et al claimed that glucose-lowering effects of glucagon-like peptide-1 receptor agonist liraglutide depend of duration of type 2 diabetes; while our resent study published in the Journal of Diabetes Investigation failed to detect such dependency. This discrepancy might be due to several reasons including co-administration of basal insulin with liraglutide in our study; ethnic difference in T2D pathophysiology between the two study; and difference in sample size (The Usui study on liraglutide/basal insulin, n = 38; the Usui study on liraglutide monotherapy or SU combination, n=88; and the Wilbrink study, n = 69).

Oral Administration of Apple Procyanidins Ameliorates Insulin Resistance via Suppression of Pro-Inflammatory Cytokine Expression in Liver of Diabetic ob/ob Mice.

Procyanidins, the main ingredient of apple polyphenols, are known to possess antioxidative and anti-inflammatory effects associated closely with the pathophysiology of insulin resistance and type 2 diabetes. We investigated the effects of orally administered apple procyanidins (APCs) on glucose metabolism using diabetic ob/ob mice. We found no difference in body weight or body composition between mice treated with APCs and untreated mice. A 4 week oral administration of APCs containing water [0.5% (w/v)] ameliorated glucose tolerance, insulin resistance, and hepatic gluconeogenesis in ob/ob mice. APCs also suppressed the increase in the level of the pancreatic ß-cell. Insulin-stimulated Akt phosphorylation was significantly enhanced; pro-inflammatory cytokine expression levels were significantly decreased, and c-Jun N-terminal kinase phosphorylation was downregulated in the liver of those mice treated with APCs. In conclusion, APCs ameliorate insulin resistance by improving hepatic insulin signaling through suppression of hepatic inflammation in ob/ob mice, which may be a mechanism with possible beneficial health effects of APCs in disturbed glucose metabolism.

Src regulates insulin secretion and glucose metabolism by influencing subcellular localization of glucokinase in pancreatic ß-cells.

AIMS/INTRODUCTION: Src, a non-receptor tyrosine kinase, regulates a wide range of cellular functions, and hyperactivity of Src is involved in impaired glucose metabolism in pancreatic ß-cells. However, the physiological role of Src in glucose metabolism in normal, unstressed ß-cells remains unclear. In the present study, we investigated the role of Src in insulin secretion and glucose metabolism. MATERIALS AND METHODS: Src was downregulated using small interfering ribonucleic acid in INS-1 cells, and glucose-induced insulin secretion, adenosine triphosphate content, intracellular calcium concentration, glucose utilization and glucokinase activity were measured. Expression levels of messenger ribonucleic acid and protein of glucokinase were examined by semiquantitative real-time polymerase chain reaction and immunoblotting, respectively. Cells were fractionated by digitonin treatment, and subcellular localization of glucokinase was examined by immunoblotting. Interaction between glucokinase and neuronal nitric oxide synthase was estimated by immunoprecipitation. RESULTS: In Src downregulated INS-1 cells, glucose-induced insulin secretion was impaired, whereas insulin secretion induced by high K(+) was not affected. Intracellular adenosine triphosphate content and elevation of intracellular calcium concentration by glucose stimulation were suppressed by Src downregulation. Src downregulation reduced glucose utilization in the presence of high glucose, which was accompanied by a reduction in glucokinase activity without affecting its expression. However, Src downregulation reduced glucokinase in soluble, cytoplasmic fraction, and increased it in pellet containing intaracellular organelles. In addition, interaction between glucokinase and neuronal nitric oxide synthase was facilitated by Src downregulation. CONCLUSIONS: Src plays an important role in glucose-induced insulin secretion in pancreatic ß-cells through maintaining subcellular localization and activity of glucokinase.

Possible link of pioglitazone with bladder cancer in Japanese patients with type 2 diabetes.

We retrospectively examined the frequency of bladder cancer in Japanese patients with type 2 diabetes in relation to use of pioglitazone. Among a total of 663 patients identified to be taking pioglitazone, 9 had bladder cancer (1.36%). Overall the hazard ratio of 1.75 [95% CI: 0.89-3.45] for pioglitazone for bladder cancer was not significant. However the prevalence of bladder cancer was 2.10% in patients taking pioglitazone for less than 24 months which was significant increased (HR 2.73 [95% CI: 1.11-6.72]).

Male gonadotroph adenoma: report of three cases and a review of the literature.

We herein report three cases of gonadotroph adenoma in men (36-72 years of age) presenting with visual impairment and suprasellar masses measuring approximately 20 to 30 mm in diameter. Endocrinological examinations were normal, except for slightly increased follicle stimulating hormone (FSH) levels in two cases. Based on the tentative diagnosis of non-functioning pituitary adenoma, transsphenoidal surgery was performed, which revealed that the tumors consisted of FSH- and LH-positive cells. As gonadotroph adenoma is very common among patients with clinically silent pituitary adenoma, it should be diagnosed using pathological examinations.

The Eradication of Helicobacter pylori does not Affect Glycemic Control in Japanese Subjects with Type 2 Diabetes.

Since infection with Helicobacter pylori has been suggested to play a pathogenic role in diabetes mellitus, we investigated whether eradication therapy for H. pylori might affect glycemic control in Japanese subjects with type 2 diabetes. A total of 72 subjects (55 males, 17 females; aged 63.7 years) with type 2 diabetes who received eradication therapy for H. pylori were included. The change of their blood glycosylated hemoglobin (A1C) levels 3 months before (-3 m) the H. pylori eradication, as well as 3 months (3 m) and 6 months (6 m) after were evaluated. Their A1C levels did not show any significant change after therapy {6.9 [0.1]% (-3 m) to 7.0 [0.1]% (3 m); P = 0.3, 7.0 [0.1] (6 m); P = 0.3}. Our findings suggest that the eradication therapy for H. pylori does not, at least profoundly, affect glycemic control in Japanese subjects with type 2 diabetes.

Relationship between telmisartan dose and glycaemic control in Japanese patients with type 2 diabetes mellitus and hypertension: a retrospective study.

BACKGROUND AND OBJECTIVES: Telmisartan has been reported to have beneficial effects on insulin resistance and lipid profiles by acting as a peroxisome proliferator-activated receptor-γ (PPARγ) agonist. In this study we investigated the relationship between telmisartan dose and glycaemic control in Japanese subjects with type 2 diabetes mellitus and hypertension. METHODS: Patients (n = 263) who were prescribed telmisartan 20, 40 or 80 mg/day at our clinic were retrospectively identified from our clinical database. Only patients without changes in their treatments for diabetes and hypertension for 6 months after starting telmisartan were included in this study. Glycosylated haemoglobin A(1c) (HbA(1c)) levels were measured at 0, 3 and 6 months after starting telmisartan. RESULTS: At 3 and 6 months after starting telmisartan, HbA(1c) levels were significantly decreased in patients treated with telmisartan 40 or 80 mg/day but not in patients treated with telmisartan 20 mg/day (mean ± standard error change at 6 months: -0.29 ± 0.10%, p < 0.001; -0.48 ± 0.15%, p < 0.001; and -0.03 ± 0.10%, p = 0.33; respectively). When patients were classified into two groups by telmisartan dose (20 vs ≥40 mg/day), there was no significant correlation between baseline HbA(1c) and change in HbA(1c) levels over time in the 20 mg/day group. However, in patients treated with ≥40 mg/day of telmisartan, baseline HbA(1c) was negatively correlated with the change in HbA(1c) at 6 months. Multiple regression analysis confirmed that baseline HbA(1c) and telmisartan dose were the predictive factors. CONCLUSION: Our results suggest that telmisartan influences glycaemic control in a dose-dependent manner; doses ≥40 mg/day may be needed to improve glycaemic control. Our data also suggest that patients with higher baseline HbA(1c) may experience greater improvements in glycaemic control with telmisartan.